Obesity is an increasing problem in the United States, with a prevalence of approximately 25% of the population. Increased visceral fat causes dysfunction of various organs and abnormal production of adipokines. Excessive body weight is a risk factor for an array of complications, including cardiovascular disease, several forms of cancer, type 2 diabetes, infertility, sexual dysfunction, and osteoarthritis. Obesity is also increasingly common in children; the rate of childhood obesity in the United States has tripled during the past 30 years. The increasing prevalence of obesity correlates with a significant increase in the prevalence of type 2 diabetes in children. Efforts to treat obesity and its related diseases and conditions, including metabolic syndrome and insulin resistance, have taken varying approaches ranging from bariatric surgery to pharmaceuticals. See, e.g., U.S. Pat. No. 5,234,454 (gastric balloon), U.S. Pat. No. 7,945,323 (stimulating the pituitary gland via an implant), and U.S. Pat. No. 6,969,702 (Exendin-4, a GLP-1 receptor agonist). However, there remains a need to identify improved methods for regulating weight gain.
Obesity is characterized by the presence of increased visceral and subcutaneous fat. The accumulation of intra-abdominal visceral fat strongly correlates with metabolic dysfunction and cardiovascular disease. The complex pathophysiology leading to excessive adipose tissue accumulation includes excessive caloric intake, reduced energy expenditure and enhanced adipogenesis. Despite the prevalence of obesity and its associated risks, few therapeutic options are available. Orlistat and Phentermine are two available pharmaceutical options available, but their efficacy is hindered long-term due to potential complications. The desire to treat and prevent obesity as well as its complications has led to considerable interest in obesity-related research.
The mass of adipose tissue is determined by a balance between energy intake and expenditure. Enhanced energy expenditure in cells can result in weight loss due to a net negative balance of caloric intake vs. caloric expenditure. Total energy expenditure includes physical activity, basal metabolism, and adaptive thermogenesis. Increased energy expenditure in adipocytes is associated with enhanced mitochondrial biogenesis and oxygen consumption. The PI3K pathway has been implicated in the regulation of energy homeostasis and can result in enhanced expression of PGC-1α. PGC-1α regulates energy homeostasis in response to environmental and nutritional stimuli. PGC-1α expression is reduced in obesity. Further, neuronal denervation has been associated with a reduction in PGC-1α expression. PGC-1α regulates multiple transcription factors to stimulate mitochondrial metabolic capacity. Mitochondrial content and oxygen consumption are reduced in the adipose tissue in high-fat diet induced obesity models. Adipocytes respond to adrenergic stimulation with catabolic reactions including lipolysis and non-shivering thermogenesis, the latter by virtue of the mitochondrial uncoupling protein-1 (UCP1) which is specifically expressed in brown adipose tissue (BAT) and regulated by β-adrenergic receptors, in particular the β3-adrenergic receptor. Anabolic functions such as lipogenesis are suppressed by adrenergic stimulation. As indicated by its name, UCP-1 uncouples oxidative phosphorylation from ATP synthesis and, instead, releases the energy stored in the proton gradient across the mitochondrial membrane as heat.
Insulin resistance occurs when peripheral tissues require an elevated amount of insulin and is associated with obesity. Although the pancreatic β cell mass is capable of increasing as insulin demand increases, its plasticity is limited. When the β cells can no longer produce sufficient insulin to meet the demand, hyperglycemia occurs and type 2 diabetes develop. Adipocytes, which are increased in the obese, are believed to play a role in this process. Adipocytes do not simply store energy; they also produce adiponectin, leptin, and various cytokines. They are believed to exert significant physiological effects, such as reducing glucose uptake in the periphery by the release of free fatty acids. Furthermore, obesity-related adipocyte apoptosis leads to inflammation, resulting in a cascade of deleterious physiological events, possibly including the inhibition of insulin signaling. Unfortunately, current anti-diabetic drugs such as thiazolidinediones are associated with further weight gain in part due to stimulation of peroxisome proliferator-activated receptor-γ (PPAR-γ) induced adipogenesis.
Glial cell line derived neurotrophic factor (GDNF) is a GDNF family receptor alpha-1 (GFRα-1) agonist, important for the differentiation and survival of neurons. GDNF signals through its receptors, including Ret and GFR-1α, by activation of the PI3K and MAPK pathways. GDNF has been contemplated as a neuromodulatory therapeutic agent for Parkinson's Disease. See, e.g., U.S. Published Patent Application No. 2008/0187522. Fu, et al. disclose intravenous treatment of experimental Parkinson's disease in the mouse with an IgG-GDNF fusion protein that penetrates the blood-brain barrier. Brain Res. 2010 Sep. 17; 1352:208-13.
The effect of neurotrophic factors on weight regulation is not entirely understood. See e.g., Bence, et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med. 2006. 12:917-924. Turner, et al. disclose hypothalamic rAAV-mediated GDNF gene delivery ameliorates age-related obesity. Neurobiol Aging. 2006 March; 27(3):459-70. The effect of GDNF weight loss was thought to be mediated via its effects on dopaminergic neurons in the hypothalamus.